Spinal neuroimmune activation and neuroinflammation following injury are associated with the development of behavioral hypersensitivity in different animal models of persistent pain states (Watkins, et al. (1995) Pain 63:289; DeLeo and Yezierski (2001) Pain 90(1-2):1-6; Winkelstein, et al. (2001) J. Comp. Neurol. 438:127-139). As such, neuroimmune activation in the central nervous system (CNS) produces glial activation and upregulation of cytokines and other regulatory proteins of the immune system (DeLeo and Yezierski (2001) supra). Spinal glial activation has been reported in rat models of neuropathy in-association with persistent behavioral hypersensitivity (Colburn, et al. (1999) Exp. Neurol. 157(2):289-304; Sweitzer, et al. (2001) J. Pharmacol. Exp. Ther. 297:1210-1217; Watkins, et al. (2001) Pain 93:201-205; Watkins, et al. (2001) Trends Neurosci. 24:450-455). Spinal cytokine (i.e., IL-1, TNF, and IL-6) mRNA and protein expression are also elevated in neuropathic injury models and exhibit a temporal relationship with behavioral hypersensitivity (DeLeo, et al. (1996) J. Interferon Cytokine Res. 16(9):695-700; Winkelstein, et al., (2001) supra; Sweitzer, et al. (2001) supra; Sweitzer, et al. (2001) Neuroscience 103:529-539). Neuroinflammation, involving the infiltration of cells into the spinal cord and DRG, occurs following nerve injury and affects behavioral hypersensitivity (Hu and McLachlan (2002) Neuroscience 112:23-28).
Emerging evidence in the literature indicates chemokines may modulate nociception (Boddeke (2001) Eur. J. Pharmacol. 429(1-3):115-119). However, while neuroinflammation implicates the upregulation of chemokines to initiate and facilitate cellular infiltration into the CNS, no study has directly investigated whether spinal chemokines are upregulated in neuropathic pain and, if so, their temporal relationship to behavioral sensitivity with this injury.
Chemokines are a subclass of cytokines involved in the activation, recruitment and infiltration of leukocytes to an injury site. They are categorized based on the presence and position of cysteine residues (Rollins (1997) Blood 90(3):909-928; Luster (1998) N. Engl. J. Med. 338(7): 436-445). Chemokines are synthesized locally at sites of inflammation and establish concentration gradients which drive target cell migration. Chemokine receptors are expressed on neurons, astrocytes and endothelial cells (Luster (1998) N. Engl. J. Med. 338(7):436-445). Cytokines, such as IL-1 and TNF, are among the main stimuli and/or modulators for chemokine production by macrophages, dendritic cells and endothelial cells (Luster, et al. (1998) supra; Andjelkovic, et al. (1999) Glia 28:225-235; Luther and Cyster (2001) Nat. Immunol. 2:102-107). This is relevant to nerve injury-induced hypersensitivity as upregulation of these same cytokines plays a crucial role in the central neuroimmune responses of persistent pain models (Watkins, et al. (1995) supra; DeLeo and Coburn (1996) supra; DeLeo, et al. (1996) In: Low Back Pain: A Scientific and Clinical Overview, Weinstein and Gordon (eds), AAOS Publishers, Rosemont, Ill., p 163-185; Hashizume, et al. (2000) Spine 25:1206-1217; Winkelstein, et al., (2001) supra). Many chemokines, including the monocyte chemoattractant proteins (MCPS), macrophage infiltrating proteins (MIPs), and regulated upon activation, normal T-cell expressed and secreted (RANTES), have all been implicated in models of direct trauma to the CNS. Furthermore, in a peripheral experimental allergic neuritis model, mRNA expression of chemokines has been characterized using quantitative PCR methods (Fujioka, et al. (1999) J. Neurovirol. 5(1):27-31). In parallel with the documented time course of symptoms in that rat neuritis model, MCP-1, MIP-1, RANTES, and IP-10 were all increased in the cauda equina. Similarly, these same chemokines (MIP-1α, MCP-1, RANTES) were rapidly upregulated in separate central inflammatory and mechanical contusion models (Ousman and David (2001) J. Neurosci. 21(13):4649-4656; Miyasgishi, et al. (1997) J. Neuroimmunol. 77 (1):17-26; McTigue, et al. (1998) J. Neurosci. Res. 53(3):368-376). In peripheral nerve injury, MCP-1 is induced in damaged tissue (Toews, et al. (1998) J. Neurosci. Res. 53(2):260-267; Coughlan, et al. (2000) Neuroscience 97(3):591-600).
Such a chemokine response remains complicated with regards to a peripheral injury, given both its potential benefits and ill-effects. As such, a balance exists between the specific neuroprotective (beneficial) and pain-promoting (harmful) responses which result as a consequence of spinal chemokine up regulation. Spinal chemokine upregulation, specifically MCP-1, which has been demonstrated to induce monocyte/macrophage infiltration in the spinal cord (McTigue, et al. (1998) supra), can induce macrophage infiltration in a beneficial effort to promote axonal repair and healing due to the peripheral injury. This upregulation, which induces macrophage and monocyte infiltration into the spinal cord, has a beneficial effect whereby these cells promote the removal of cellular debris and facilitate axonal regeneration (Scheidt, et al. (1986) Brain Res. 379(2):380-384; Avellino, et al. (1995) Exp. Neurol. 136(2):183-198; Zeev-Brann, et al. (1998) Glia 23(3):181-190; Ma, et al. (2002) J. Neurosci. Res. 68(6):691-702). In addition, infiltrating macrophages secrete anti-inflammatory cytokines which help to reduce the overall central inflammatory response. Together, these actions of promoting axonal recovery and improved cellular survival push this “balance” to a more reparative one, which may be beneficial in achieving a state of functional survival in the CNS. In contrast, however, these same cells also contribute deleterious effects to CNS tissue influencing the balance towards a more harmful response, and can contribute to the maintenance of a pain response. Macrophages produce a host of neurotoxic mediators, including nitric oxide (Grzybicki, et al. (1998) Acta Neuropathol. (Berl). 95(1):98-103; Yamanaka, et al. (1998) Neurosci. Res. 31(4):347-350) and inflammatory cytokines, which further contribute to a deleterious cascade leading to secondary cellular damage in the spinal cord. Moreover, this same deleterious effect may contribute to the maintenance of persistent pain.
Several groups of compounds are used to relieve pain, depending on the severity and duration of the pain sensation, and on the nature of the painful stimulus. Drugs used to relieve mild, moderate or severe pain without causing unconsciousness are generally called analgesics. Mild analgesics that are termed non-narcotic agents include aspirin, acetaminophen and non-steroidal anti-inflammatory drugs. Should non-narcotic-based agents prove ineffective, narcotic/opioid analgesic agents such as morphine, codeine, meperidine, and the like are used to treat more severe acute or chronic forms of pain (Wingard, et al. (1991) Human Pharmacology: Molecular to Clinical, Mosby-Year Book, Inc., pp. 383, 391-92).
Despite the sophistication of new analgesic agents and improved understanding of the neurobiological basis of pain, current pain management treatment modalities involving narcotic, non-narcotic, and anxiolytic therapeutic agents have not been able to manage the side effect issues associated with the use of these agents. In addition, as the dizziness, drowsiness, depression, lethargy, difficulty in being mobile, weakness in the extremities, orthostatic hypotension, respiratory depression, gastrointestinal distress, and renal distress side effects of these agents occur, therapeutic regimens frequently discontinue one agent for a less successful pain control agent. Patients experiencing side effects become mal- or non-compliant in taking the prescribed pain treatment regimen to manage their particular type of pain. Finally, because of the depressive effects of these agents, healthcare personnel treat patient populations of this type more on an in-patient only setting to minimize liability issues and to monitor abuse potentials by such patients taking these particular medications.
Thus, there is a need for improved methods of treating or preventing pain.